title: Leveraging nanochannels for universal, zero-order drug delivery in vivo.
abstract: Drug delivery is essential to achieve effective therapy. Herein we report on the only implantable nanochannel membrane with geometrically defined channels as small as 2.5 nm that achieves constant drug delivery in vivo. Nanochannels passively control the release of molecules by physico-electrostatic confinement, thereby leading to constant drug diffusion. We utilize a novel design algorithm to select the optimal nanochannel size for each therapeutic agent. Using nanochannels as small as 3.6 and 20 nm, we achieve sustained and constant plasma levels of leuprolide, interferon α-2b, letrozole, Y-27632, octreotide, and human growth hormone, all delivered at clinically-relevant doses. The device was demonstrated in dogs, rats, and mice and was capable of sustaining target doses for up to 70 days. To provide evidence of therapeutic efficacy, we successfully combined nanochannel delivery with a RhoA pathway inhibitor to prevent chronic rejection of cardiac allografts in a rat model. Our results provide evidence that the nanochannel platform has the potential to dramatically improve long-term therapies for chronic conditions.
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Ave, Houston 77030, USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferrati
authors.forename: Daniel
authors.initials: D
authors.lastname: Fine
authors.forename: Junping
authors.initials: J
authors.lastname: You
authors.forename: Enrica
authors.initials: E
authors.lastname: De Rosa
authors.forename: Lee
authors.initials: L
authors.lastname: Hudson
authors.forename: Erika
authors.initials: E
authors.lastname: Zabre
authors.forename: Sharath
authors.initials: S
authors.lastname: Hosali
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Catherine
authors.initials: C
authors.lastname: Hickman
authors.forename: Shyam
authors.initials: S
authors.lastname: Sunder Bansal
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cordero-Reyes
authors.forename: Thomas
authors.initials: T
authors.lastname: Geninatti
authors.forename: Juliana
authors.initials: J
authors.lastname: Sih
authors.forename: Randy
authors.initials: R
authors.lastname: Goodall
authors.forename: Ganesh
authors.initials: G
authors.lastname: Palapattu
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kloc
authors.forename: Rafik M
authors.initials: RM
authors.lastname: Ghobrial
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Alessandro
authors.initials: A
authors.lastname: Grattoni
mesh_terms: D000818:Animals; D004285:Dogs; D016503:Drug Delivery Systems / Q000295:instrumentation*; D004867:Equipment Design; D005260:Female; D006801:Humans; D008297:Male; D008567:Membranes, Artificial; D051379:Mice; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D019736:Prostheses and Implants; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008567:Membranes, Artificial; D004364:Pharmaceutical Preparations
keywords: Drug delivery; Implantable device; Nanochannel; Transplantation